Endothelins are vasoactive peptides comprising 21 amino acid residues, are isolated from endothelial cells, and associates with homeostasis of a circulatory system. Endothelins act as aggravation factors of cardiovascular diseases such as hypertension, pulmonary hypertension, stroke, cerebrovascular spasm, acute renal insufficiency, acute proliferative nephropathy, acute myocardial infarction, chronic heart failure, vascular intimal thickness and the like by the medium of endothelin receptors.
Two kinds of receptor subtypes, an endothelin A and an endothelin B receptors, are known and three types of receptor antagonists, A-selective, B-selective and A & B non-selective antagonists, have been presumed to exist. Although there remain many unknown matters about what kind of diseases are associated with any type of receptors, they have been gradually made clear. For example, an endothelin A receptor is considered to be associated with acute and chronic diseases such as hypertension, pulmonary hypertension, cerebral stroke, cerebrovascular spasm, cerebral edema, acute renal insufficiency, myocardial infarction, chronic heat insufficiency, asthma and the like and therefore, the antagonists have been expected to be useful for treatment of these diseases. There is a possibility that an endothelin B receptor is associated with the appearance and progression of cardiovascular disease and further, it is considered to associate with metabolism of endothelin in blood, the vascular intimal thickness and development and differentiation of a certain kind of cells.
Peptide-type antagonists have been developed as endothelin receptor antagonists but there are many problems for application as a medicament of chronic diseases. For example, they tend to be readily metabolized in the living body, the duration of action is short, and they are not effective in oral administration and the like. Endothelin is associated with diverse diseases, the effect is potent and the mechanism of action is complicated. Accordingly, development of a non-peptide type endothelin antagonist having a long duration of action and a superior oral availability has been desired.
Indan and inden derivatives are disclosed in JP-A 7-501322 and WO 94/25013 as an endothelin receptor antagonist but the data of pharmacological activities indicating effectiveness of these derivatives as medicaments have not been disclosed.
Arteriosclerosis is caused by a combination of many risk factors and injury factors and one of the examples of risk factors is cholesterol. Law density cholesterol (hereinafter referred to as LDL) is oxidized after accumulation on artery walls, taken in macrophages and the macrophages turn foam cells. It is considered that accumulation of foam cell forming-macrophages accelerates the proliferation of smooth muscle cells and cell intimal fibrous thickness and finally leads up to an atherosclerotic lesion. According to these knowledge, a macrophage foam cell formation inhibitor is expected to be effective for treating and/or preventing the atherosclerosis.
The endothelin antagonists are generally supposed to have an anti-arteriosclerosis activity and the mechanism has been considered to be related to a thrombus formation caused by vasoconstriction or to a proliferation promoting effect on a vascular smooth muscle cell. With regard to an inhibition of macrophage foam cell formation, only BMS-182874 has been disclosed to reduce the number and size of foam cells (American Journal of Pathology vol. 146, No.4, 819-826 (1995)).
Compounds having similar structure have been disclosed in JP-A 60-149580 and JP-A 60-149581 but their endothelin antagonistic activity is not suggested at all.